The present invention relates to combinations of antiseptic and antibiotic agents which exert an antimicrobial effect while deterring, relative to other antimicrobial agents, the development of antibiotic-resistant microorganisms.
An antiseptic is a substance that kills or prevents the growth of microorganisms, and which is typically applied to living tissue, distinguishing the class from disinfectants, which are usually applied to inanimate objects (Goodman and Gilman""s xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d, Seventh Edition, Gilman et al., editors, 1985, Macmillan Publishing Co., (hereafter, Goodman and Gilmanxe2x80x9d) pp. 959-960). Common examples of antiseptics are ethyl alcohol and tincture of iodine. Alcohol is usually used to clean a subject""s skin prior to insertion of a hypodermic needle; tincture of iodine is frequently applied as a first step in wound care, both uses intended to decrease the number of microbes on the skin to prevent invention.
While antiseptics once played a more substantial role in wound management, they are now secondary in importance to antibiotics, chemical substances produced by various species of microorganisms (or synthetic or semisynthetic analogs thereof) that kill or suppress the growth of other microorganisms (Goodman and Gilman, p. 1067). Antibiotics may be administered systemically or locally applied. Since the production of penicillin in 1941, antibiotics have been widely used, with the result that microorganism strains have developed which are resistant to one or more antibiotic. The generation of resistant organisms has created an ever-increasing need for the identification or synthesis of new antibiotics (Goodman and Gilman, p. 1066).
One particularly useful class of antibiotics is tetracyclines, which exert their antibacterial action by binding to microbial ribosomes and preventing protein synthesis (Goodman and Gilman, p.1171). Tetracyclines are primarily bacteriostatic when tested in vitro, and only multiplying microorganisms are affected. They possess antimicrobial activity against a wide variety of microorganisms, including gram-positive and gram negative bacteria, and against some microorganisms, such as Rickettsiae, Mycoplasma, Chlamydia, some atypical Mycobacteria, and ameobae, that are resistant to other classes of antibiotics (Id.). Minocycline, doxycycline, tetracycline and oxytetracycline are tetracycline-class drugs listed in order of decreasing antimicrobial activity (Id.).
The first documented medical use of bismuth occurred in 1773, when it was used in salves. Since then it has been used to combat diarrhea, gastroenteritis, stomach cramps, vomiting and ulcers. It has been used for the treatment of surgical wounds (Bierer, 1990, Rev. Infect. Dis. 12 (Suppl. 1): S3-S8). The antimicrobial effect of bismuth is well known. The reducing effect of bismuth compounds on fermentation by colonic bacteria has been demonstrated both in vitro and in vivo (Leon-Barua et al., 1990, Rev. Infect. Dis. 12 (Suppl. 1): S24-S29).
Bismuth salts have also been shown to have a significant effect on the inhibitory activity of antibiotics. Bismuth salicylate (xe2x80x9cBSSxe2x80x9d) and bismuth nitrate have been reported to potentiate aminoglycoside activity against gram negative bacteria (Domenico et al., 1991, J. Antimicrob. Chemother. 28:801-810). BSS, bismuth nitrate and bismuth dimercaprol (Bis-BAL), have also been reported to inhibit capsular polysaccharide production by the bacterium Klebsiella pneumoniae (Domenico et al., 1991, J. Antimicrobial Chemother. 28:801-810; Domenico et al., 1996, Ann. N. Y. Acad. Sci. 797:269-270). BisBAL has also been shown to have good activity against a wide spectrum of bacteria among the genera Yersinia, Shigella, Salmonella, Pseudomonas, Proteus, Enterobacter, Escherichia, Staphylococci, Helicobacter, and Clostridia (Domenico, 1997, Antimicrob. Ag. Chemother. 41:1697-1703) and to inhibit polysaccharide production in biofilms (Huang and Stewart, 1999, J. Antimicrob. Chemother. 44:601-605). The use of bismuth salts in combination with thiol compounds for the preparation of a composition with anti-infective properties has been described by Domenico, 1999, U.S. Pat. No. 5,928,671. The potentiation of antibiotics by a bismuth salt of pyrrolidone carboxylic acid, resulting in higher tissue levels of the antibiotic was described by Bocher et al., 1977, U.S. Pat. No. 4,064,238. The use of bismuth salts, in combination with an antibiotic and metronidazole for the eradication of Helicobacter pylori, a causative agent of duodenal ulcer, has also been described (Borody, 1993, U.S. Pat. No. 5,196,205).
International Application No. PCT/US00/08692, entitled xe2x80x9cTRICLOSAN AND SILVER COMPOUND CONTAINING MEDICAL DEVICESxe2x80x9d by The Trustees of Columbia University in the City of New York teaches the addition of various antibiotics, including those set forth herein, to combinations of triclosan and silver salts. The use of bismuth salts, as set forth herein, was not disclosed.
The present invention relates to compositions comprising a combination of one or more antiseptic and an antibiotic. It is based, at least in part, on the discovery that such combinations tend to deter the formation of antibiotic-resistant organisms. In preferred, nonlimiting embodiments of the invention, the antibiotic is minocycline and the antiseptic is a chlorhexidine compound, triclosan, or benzalkonium chloride, and in particular embodiments, a silver salt or a bismuth salt is added. Examples of specific, nonlimiting embodiments of the invention include combinations of (i) minocycline, triclosan, and a bismuth salt; (ii) minocycline, a chlorhexidine compound, and a bismuth salt; and (iii) minocycline, benzalkonium chloride, and a bismuth salt. The present invention further provides for articles, such as, but not limited to, medical articles, which have been treated with or which otherwise comprise a combination of antiseptic and antibiotic.
Antibiotics, unlike antiseptics, may be used in relatively high concentrations because they tend to be less toxic to host tissue. The use of higher concentrations may result in longer term efficacy. In contrast, antiseptics typically should be used in lower concentrations, because they are frequently toxic to host tissue. Even at lower concentrations, however, antiseptics may provide cidal action against a wide range of microorganisms. Thus, combinations of antibiotics and antiseptics according to the invention may provide for prolonged antimicrobial effectiveness against a variety of microbes.
The present invention relates to compositions comprising combinations of (i) an antibiotic selected from the group consisting of minocycline, rifampin, and norfloxacin; and (ii) an antiseptic selected from the group consisting of biguanide compounds, triclosan, and benzalkonium chloride. In preferred embodiments, such compositions further comprise a salt of bismuth, cerium, or zinc or a silver-containing compound. Such compositions may be incorporated into or onto medical devices to impart antimicrobial activity to the devices. The present invention also provides for methods of using such compositions in the preparation of medical devices.
Biguanide compounds which may be used according to the invention include poly (hexamethylene biguanide) hydrochloride and chlorhexidine compounds. Chlorhexidine is the term denoting the chemical compound 1,6 bis(N5-p-chlorophenyl-N1-biguanido)hexane). Chlorhexidine compounds include chlorhexidine free base (xe2x80x9cCHXxe2x80x9d) as well as chlorhexidine salts, such as chlorhexidine diphosphanilate, chlorhexidine digluconate (xe2x80x9cCHGxe2x80x9d), chlorhexidine diacetate (xe2x80x9cCHAxe2x80x9d), chlorhexidine dihydrochloride, chlorhexidine dichloride, chlorhexidine dihydroiodide, chlorhexidine diperchlorate, chlorhexidine dinitrate, chlorhexidine sulfate, chlorhexidine sulfite, chlorhexidine thiosulfate, chlorhexidine di-acid phosphate, chlorhexidine difluorophosphate, chlorhexidine diformate, chlorhexidine dipropionate, chlorhexidine di-iodobutyrate, chlorhexidine di-n-valerate, chlorhexidine dicaproate, chlorhexidine malonate, chlorhexidine succinate, chlorhexidine malate, chlorhexidine tartrate, chlorhexidine dimonoglycolate, chlorhexidine mono-diglycolate, chlorhexidine dilactate, chlorhexidine di-xcex1-hydroxyisobutyrate, chlorhexidine diglucoheptonate, chlorhexidine di-isothionate, chlorhexidine dibenzoate, chlorhexidine dicinnamate, chlorhexidine dimandelate, chlorhexidine di-isophthalate, chlorhexidine di-2-hydroxy-napthoate, and chlorhexidine embonate.
Bismuth salts which may be used according to the invention include bismuth nitrate, bismuth citrate, bismuth salicylate, bismuth borate, bismuth mandelate, bismuth palmitate, bismuth benzoate, and bismuth sulfadiazine.
Cerium salts which may be used according to the invention include cerium nitrate and other cerium salts having a water solubility similar to cerium nitrate.
The term silver-containing compound, as used herein, refers to a compound comprising silver, either in the form of a silver atom or a silver ion unlinked or linked to another molecule via a covalent or noncovalent (e.g., ionic) linkage, including but not limited to covalent compounds such as silver sulfadiazine (xe2x80x9cAgSDxe2x80x9d) and silver salts such as silver oxide (xe2x80x9cAg2Oxe2x80x9d), silver carbonate (xe2x80x9cAg2CO3xe2x80x9d), silver deoxycholate, silver salicylate, silver iodide, silver nitrate (xe2x80x9cAgNO3xe2x80x9d), silver paraaminobenzoate, silver paraaminosalicylate, silver acetylsalicylate, silver ethylenediaminetetraacetic acid (xe2x80x9cAg EDTAxe2x80x9d), silver picrate, silver protein, silver citrate, silver lactate and silver laurate.
Zinc salts which may be used according to the invention include zinc acetate and other zinc salts having a water solubility similar to zinc acetate.
The present invention provides for the incorporation of combinations of the foregoing elements into or onto medical devices, and for the medical devices which incorporate said combinations. The terms xe2x80x9cmedical articlexe2x80x9d and xe2x80x9cmedical devicexe2x80x9d are used interchangeably herein. Medical articles that may be treated according to the invention are either fabricated from or coated or treated with biomedical polymer (and hence may be referred to as xe2x80x9cpolymer-containing medical articlesxe2x80x9d) and include, but are not limited to, catheters including urinary catheters and vascular catheters (e.g., peripheral and central vascular catheters), wound drainage tubes, arterial grafts, soft tissue patches (such as polytetrafluoroethylene (xe2x80x9cPTFExe2x80x9d) soft tissue patches), gloves, shunts, stents, tracheal catheters, wound dressings, sutures, guide wires and prosthetic devices (e.g., heart valves and LVADs). Vascular catheters which may be prepared according to the present invention include, but are not limited to, single and multiple lumen central venous catheters, peripherally inserted central venous catheters, emergency infusion catheters, percutaneous sheath introducer systems and thermodilution catheters, including the hubs and ports of such vascular catheters.
In particular embodiments, the combinations of the invention may be incorporated into or onto a medical device by exposing the device to a treatment solution comprising the combination in an appropriate solvent system. Said treatment solutions fall within the scope of compositions covered by the present invention. Where the treatment solution contains minocycline, the concentration of minocycline is between 1 and 8 percent weight/volume (w/v), and preferably between 3 and 5 percent (w/v); where the treatment solution contains rifampin, the concentration of rifampin is between 1 and 8 percent (w/v), and preferably between 3 and 5 percent (w/v); where the treatment solution contains norfloxacin, the concentration of norfloxacin is between 1 and 8 percent (w/v) and preferably between 3 and 5 percent (w/v); where the solution contains a chlorhexidine compound, the concentration of chlorhexidine compound is between 1 and 8 percent (w/v) and preferably between 3 and 5 percent (w/v); where the treatment solution contains triclosan, the concentration is between 1 and 8 percent (w/v) and preferably between 3 and 5 percent (w/v); where the treatment solution contains benzalkonium chloride, the concentration of benzalkonium chloride (xe2x80x9cBZKxe2x80x9d) is between 0.25 and 1 percent (w/v) and preferably is 0.5 percent (w/v); where the treatment solution contains a bismuth salt, the concentration of bismuth salt is between 0.5 and 2 percent (w/v) and preferably is 2 percent (w/v); where the treatment solution contains a cerium salt, the concentration of cerium salt is preferably between 1 and 5 percent (w/v); where the treatment solution contains a zinc salt, the concentration of zinc salt is between 1 and 5 percent (w/v) and preferably is 2 percent (w/v); and where the treatment solution contains a silver-containing compound, the concentration of silver-containing compound is between 0.5 and 2 percent (w/v) and preferably is 1 percent. The above ranges, e.g. xe2x80x9cbetween X percent and Y percentxe2x80x9d, include the boundary values X and Y and are intended herein to encompass variations of 20 percent of the value of X and Y, in other words, the ranges should be interpreted to mean xe2x80x9cbetween Xxc2x10.20X and Yxc2x10.20Yxe2x80x9d.
An appropriate solvent system is a solvent system which will either solubilize or, less desirably, produce a suspension of anti-infective agents, which will preferably result in slight swelling of the medical device (to facilitate incorporation of anti-infective agents), but which will preferably not substantially alter the surface of the medical device (e.g., render the surface rough) so as not to impair the clinical usefulness of the device. Specific non-limiting examples of solvent systems include 70 percent (volume/volume; xe2x80x9cv/vxe2x80x9d) tetrahydrofuran (xe2x80x9cTHFxe2x80x9d) and 30 percent (v/v) methanol (xe2x80x9cMeOHxe2x80x9d), and more preferably, for dissolving an antibiotic, 50 percent (v/v) tetrahydrofuran (xe2x80x9cTHFxe2x80x9d) and 50 percent (v/v) methanol. Such treatment solutions may further comprise a biomedical polymer. As specific, non-limiting examples, the treatment solution may comprise 3 percent (w/v) 93A polyurethane and 1 percent (w/v) 60D polyurethane or 1 percent (w/v) 93A polyurethane and 3 percent (w/v) 60D polyurethane.
For example, a polyurethane catheter may be exposed to a treatment solution of the invention (by dipping and/or drawing treatment solution through the catheter lumen) for between 2 and 200 seconds, and preferably between 2 and 100 seconds, and then dried at room temperature. A polyurethane catheter treated in this manner using 1:1 THF/MeOH as a solvent system would contain the following amounts of anti-infective substances (where the term xe2x80x9canti-infectivexe2x80x9d refers to antibiotics and antiseptics): where the catheter contains contains minocycline, the amount of minocycline is between 100 and 450 micrograms per centimeter; where the catheter contains rifampin, the amount of rifampin is between 100 and 450 micrograms per centimeter; where the catheter contains norfloxacin, the amount of norfloxacin is between 100 and 450 micrograms per centimeter; where the catheter contains a chlorhexidine compound, the amount of chlorhexidine compound is between 130 and 520 micrograms per centimeter; where the catheter contains triclosan, the amount is between 130 and 750 micrograms per centimeter; where the catheter contains benzalkonium chloride, the amount of benzalkonium chloride (xe2x80x9cBZKxe2x80x9d) is between 25 and 100 micrograms per centimeter; where the catheter contains a bismuth salt, the amount of bismuth salt is between 50 and 300 micrograms per centimeter; where the catheter contains a cerium salt, the amount of cerium salt is between 50 and 200 micrograms per centimeter; where the catheter contains a zinc salt, the amount of zinc salt is between 50 and 200 micrograms per centimeter; and where the catheter contains a silver-containing compound, the amount of silver-containing compound is between 25 and 300 micrograms per centimeter. Furthermore, the present invention provides for catheters and other medical devices comprising the abovementioned amounts of anti-infective agents in the inventive combinations whether they have been prepared using such a treatment solution or by other means, such as by extrusion, by xe2x80x9cpaintingxe2x80x9d a coating solution comprising the inventive combinations, by coating with a powder comprising the inventive combinations, etc.
Examples of combinations covered by the present invention include, but are not limited to, the following:
minocycline and bismuth;
minocycline and chlorhexidine free base;
minocycline and chlorhexidine diacetate;
minocycline and chlorhexidine digluconate;
minocycline and triclosan;
minocycline, chlorhexidine free base and bismuth nitrate;
minocycline, chlorhexidine diacetate, and bismuth nitrate;
minocycline, chlorhexidine digluconate, and bismuth nitrate;
minocycline, triclosan and bismuth nitrate;
minocycline, chlorhexidine free base, and benzalkonium chloride;
minocycline, chlorhexidine diacetate and benzalkonium chloride;
minocycline, chlorhexidine digluconate and benzalkonium chloride;
minocycline, triclosan and benzalkonium chloride;
minocycline, chlorhexidine free base, and benzalkonium chloride;
minocycline, chlorhexidine diacetate and benzalkonium chloride;
minocycline, chlorhexidine digluconate and benzalkonium chloride;
minocycline, triclosan and benzalkonium chloride;
minocycline, chlorhexidine free base, bismuth nitrate and benzalkonium chloride;
minocycline, chlorhexidine diacetate, bismuth nitrate and benzalkonium chloride;
minocycline, triclosan and silver carbonate;
minocycline, chlorhexidine digluconate, bismuth nitrate and benzalkonium chloride; and
minocycline, triclosan, bismuth nitrate and benzalkonium chloride.